JP2012531204A5 - - Google Patents

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JP2012531204A5
JP2012531204A5 JP2012517730A JP2012517730A JP2012531204A5 JP 2012531204 A5 JP2012531204 A5 JP 2012531204A5 JP 2012517730 A JP2012517730 A JP 2012517730A JP 2012517730 A JP2012517730 A JP 2012517730A JP 2012531204 A5 JP2012531204 A5 JP 2012531204A5
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oligonucleotide
tnfr2
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factor receptor
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in vivoまたはin vitroで患者の細胞または組織における腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドの機能および/または発現を調節するための組成物であって、
配列番号2のヌクレオチド1〜413および配列番号3のヌクレオチド1〜413中の連続した5〜30ヌクレオチドを含むポリヌクレオチドの逆相補物に少なくとも50%の配列同一性を有する長さ5〜30ヌクレオチドの少なくとも1つのアンチセンスオリゴヌクレオチドを含む組成物。 A composition for modulating tumor necrosis factor receptor 2 (TNFR2) polynucleotide function and / or expression in a patient cell or tissue in vivo or in vitro comprising:
5-30 nucleotides in length having at least 50% sequence identity to the reverse complement of a polynucleotide comprising nucleotides 1-313 of SEQ ID NO: 2 and 5-30 nucleotides consecutive in nucleotides 1-413 of SEQ ID NO: 3 composition comprising at least one antisense oligonucleotide de. in vivoまたはin vitroで患者の細胞または組織における腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドの機能および/または発現を調節するための組成物であって、
腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドの天然アンチセンスの逆相補物に少なくとも50%の配列同一性を有する長さ5〜30ヌクレオチドの少なくとも1つのアンチセンスオリゴヌクレオチドを含む組成物。 A composition for modulating tumor necrosis factor receptor 2 (TNFR2) polynucleotide function and / or expression in a patient cell or tissue in vivo or in vitro comprising:
Tumor Necrosis Factor Receptor 2 (TNFR2) polynucleotide composition reverse complement of natural antisense comprising at least one antisense oligonucleotide de lengths 5-30 nucleotides having at least 50% sequence identity. in vivoまたはin vitroで患者の細胞または組織における腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドの機能および/または発現を調節するための組成物であって、
腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドに対するアンチセンスオリゴヌクレオチドに少なくとも50%の配列同一性を有する少なくとも1つの長さ5〜30ヌクレオチドのアンチセンスオリゴヌクレオチドを含む組成物。 A composition for modulating tumor necrosis factor receptor 2 (TNFR2) polynucleotide function and / or expression in a patient cell or tissue in vivo or in vitro comprising:
Tumor Necrosis Factor Receptor 2 (TNFR2) a composition comprising an antisense oligonucleotide de of at least one length 5-30 nucleotides having at least 50% sequence identity to an antisense oligonucleotide to the polynucleotide. in vivoまたはin vitroで患者の細胞または組織における腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドの機能および/または発現を調節するための組成物であって、
腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドの天然アンチセンスオリゴヌクレオチドの領域を標的にする少なくとも1つのアンチセンスオリゴヌクレオチドを含む組成物。 A composition for modulating tumor necrosis factor receptor 2 (TNFR2) polynucleotide function and / or expression in a patient cell or tissue in vivo or in vitro comprising:
Tumor Necrosis Factor Receptor 2 (TNFR2) composition regions of natural antisense oligonucleotides of a polynucleotide comprising at least one antisense oligonucleotide de targeting. 腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドの機能および/または発現が対照と比較してin vivoまたはin vitroで増大する、請求項4に記載の組成物。 5. The composition of claim 4, wherein the function and / or expression of a tumor necrosis factor receptor 2 (TNFR2) polynucleotide is increased in vivo or in vitro compared to a control. 少なくとも1つのアンチセンスオリゴヌクレオチドが腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドの天然アンチセンス配列を標的にする、請求項4に記載の組成物。 5. The composition of claim 4, wherein the at least one antisense oligonucleotide targets the natural antisense sequence of a tumor necrosis factor receptor 2 (TNFR2) polynucleotide. 少なくとも1つのアンチセンスオリゴヌクレオチドが腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドのコードおよび/または非コード核酸配列を含む核酸配列を標的にする、請求項4に記載の組成物。 5. The composition of claim 4, wherein the at least one antisense oligonucleotide targets a nucleic acid sequence comprising a coding and / or non-coding nucleic acid sequence of a tumor necrosis factor receptor 2 (TNFR2) polynucleotide. 少なくとも1つのアンチセンスオリゴヌクレオチドが腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドのオーバーラップおよび/または非オーバーラップ配列を標的にする、請求項4に記載の組成物。 5. The composition of claim 4, wherein the at least one antisense oligonucleotide targets overlapping and / or non-overlapping sequences of tumor necrosis factor receptor 2 (TNFR2) polynucleotides. 少なくとも1つのアンチセンスオリゴヌクレオチドが、少なくとも1つの修飾された糖部分、少なくとも1つの修飾されたヌクレオシド間結合、少なくとも1つの修飾されたヌクレオチドおよびそれらの組み合わせから選択される1つまたは複数の修飾を含む、請求項4に記載の組成物。 At least one antisense oligonucleotide has one or more modifications selected from at least one modified sugar moiety, at least one modified internucleoside linkage, at least one modified nucleotide, and combinations thereof. 5. The composition of claim 4, comprising. 1つまたは複数の修飾が2'-O-メトキシエチル修飾糖部分、2'-メトキシ修飾糖部分、2'-O-アルキル修飾糖部分、二環性糖部分およびそれらの組み合わせから選択される少なくとも1つの修飾された糖部分を含む、請求項9に記載の組成物。 At least one or more modifications are selected from 2'-O-methoxyethyl modified sugar moieties, 2'-methoxy modified sugar moieties, 2'-O-alkyl modified sugar moieties, bicyclic sugar moieties and combinations thereof 10. A composition according to claim 9, comprising one modified sugar moiety. 1つまたは複数の修飾がホスホロチオエート、2'-O-メトキシエチル(MOE)、2'-フルオロ、アルキルホスホネート、ホスホロジチオエート、アルキルホスホノチオエート、ホスホラミデート、カルバミン酸、炭酸、リン酸トリエステル、アセトアミデート、カルボキシメチルエステルおよびそれらの組み合わせから選択される少なくとも1つの修飾されたヌクレオシド間結合を含む、請求項9に記載の組成物。 One or more modifications are phosphorothioate, 2'-O-methoxyethyl (MOE), 2'-fluoro, alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamic acid, carbonic acid, triphosphate 10. The composition of claim 9, comprising at least one modified internucleoside linkage selected from esters, acetamidates, carboxymethyl esters and combinations thereof . 1つまたは複数の修飾が、ペプチド核酸(PNA)、ロックド核酸(LNA)、アラビノ核酸(FANA)、それらの類似体、誘導体および組み合わせから選択される少なくとも1つの修飾されたヌクレオチドを含む、請求項9に記載の組成物。 The one or more modifications comprise at least one modified nucleotide selected from peptide nucleic acids (PNA), locked nucleic acids (LNA), arabino nucleic acids (FANA), analogs, derivatives and combinations thereof. 9. The composition according to 9. 少なくとも1つのオリゴヌクレオチドが少なくとも1つの配列番号4〜10に記載のオリゴヌクレオチド配列を含む、請求項1に記載の組成物。 The composition of claim 1, wherein the at least one oligonucleotide comprises at least one oligonucleotide sequence set forth in SEQ ID NOs: 4-10. in vivoまたはin vitroで哺乳動物の細胞または組織における腫瘍壊死因子受容体2(TNFR2)の機能および/または発現を調節するための組成物であって、
腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドのアンチセンスおよび/またはセンス核酸分子の少なくとも5個の連続する核酸の相補配列に少なくとも50%の配列同一性を有する、腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドのアンチセンスポリヌクレオチドに特異的な、長さ5〜30ヌクレオチドの少なくとも1つの低分子干渉RNA(siRNA)オリゴヌクレオチドを含む組成物。 A composition for modulating tumor necrosis factor receptor 2 (TNFR2) function and / or expression in mammalian cells or tissues in vivo or in vitro comprising:
Tumor Necrosis Factor Receptor 2 (TNFR2) also reduced the antisense and / or sense nucleic acid molecule of polynucleotide having at least 50% sequence identity to the five complementary sequence of contiguous nucleic acids, tumor necrosis factor receptor 2 (TNFR2) polynucleotide antisense polynucleotide specific for at least one small interfering RNA (siRNA) composition comprising an oligonucleotide de lengths 5-30 nucleotides. 前記オリゴヌクレオチドが、腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドのアンチセンスおよび/またはセンス核酸分子に相補的である少なくとも5個の連続する核酸の配列に少なくとも80%の配列同一性を有する、請求項14に記載の組成物。 Said oligonucleotide, tumor necrosis factor receptor 2 (TNFR2) polynucleotide antisense and / or at least 80% sequence identity to the sequence of a nucleic acid also five continuous with less which is complementary to a sense nucleic acid molecule 15. A composition according to claim 14, comprising: in vivoまたはin vitroで哺乳動物の細胞または組織における腫瘍壊死因子受容体2(TNFR2)の機能および/または発現を調節するための組成物であって、
配列番号1〜3に記載の少なくとも1つの核酸配列に少なくとも50%の配列同一性を有する、腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドのセンスおよび/または天然アンチセンス鎖の非コードおよび/またはコード配列に特異的な、長さ5〜30ヌクレオチドの少なくとも1つのアンチセンスオリゴヌクレオチドを含む組成物。 A composition for modulating tumor necrosis factor receptor 2 (TNFR2) function and / or expression in mammalian cells or tissues in vivo or in vitro comprising:
Non-coding and / or non-coding of the sense and / or natural antisense strand of the tumor necrosis factor receptor 2 (TNFR2) polynucleotide having at least 50% sequence identity to at least one nucleic acid sequence set forth in SEQ ID NOs: 1-3 coding sequence specific, length 5-30 compositions comprising at least one antisense oligonucleotide de nucleotides. 少なくとも1つの修飾を含む合成修飾オリゴヌクレオチドであって、少なくとも1つの修飾が、少なくとも1つの修飾された糖部分、少なくとも1つの修飾されたヌクレオチド間結合、少なくとも1つの修飾されたヌクレオチド、およびそれらの組み合わせから選択され、腫瘍壊死因子受容体2(TNFR2)遺伝子にハイブリダイズし、かつ正常対照と比較してin vivoまたはin vitroで腫瘍壊死因子受容体2(TNFR2)遺伝子の機能および/または発現を調節するアンチセンス化合物であるオリゴヌクレオチド。   A synthetic modified oligonucleotide comprising at least one modification, wherein at least one modification comprises at least one modified sugar moiety, at least one modified internucleotide linkage, at least one modified nucleotide, and their Selected from the combination, hybridizes to the tumor necrosis factor receptor 2 (TNFR2) gene, and functions and / or expresses the tumor necrosis factor receptor 2 (TNFR2) gene in vivo or in vitro compared to normal controls Oligonucleotides that are antisense compounds that modulate. 少なくとも1つの修飾が、ホスホロチオエート、アルキルホスホネート、ホスホロジチオエート、アルキルホスホノチオエート、ホスホラミデート、カルバミン酸、炭酸、リン酸トリエステル、アセトアミデート、カルボキシメチルエステルおよびそれらの組み合わせからなる群から選択されるヌクレオチド間結合を含む、請求項17に記載のオリゴヌクレオチド。   At least one modification is from the group consisting of phosphorothioate, alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamic acid, carbonic acid, phosphate triester, acetamidate, carboxymethyl ester and combinations thereof 18. An oligonucleotide according to claim 17 comprising selected internucleotide linkages. 少なくとも1つのホスホロチオエートヌクレオチド間結合を含む、請求項17に記載のオリゴヌクレオチド。   18. The oligonucleotide of claim 17, comprising at least one phosphorothioate internucleotide linkage. ホスホロチオエートヌクレオチド間結合の骨格を含む、請求項17に記載のオリゴヌクレオチド。   18. The oligonucleotide of claim 17, comprising a phosphorothioate internucleotide linkage backbone. ペプチド核酸、ロックド核酸(LNA)、類似体、誘導体、およびそれらの組み合わせから選択される少なくとも1つの修飾されたヌクレオチドを含む、請求項17に記載のオリゴヌクレオチド。   18. The oligonucleotide of claim 17, comprising at least one modified nucleotide selected from peptide nucleic acids, locked nucleic acids (LNA), analogs, derivatives, and combinations thereof. ホスホロチオエート、アルキルホスホネート、ホスホロジチオエート、アルキルホスホノチオエート、ホスホラミデート、カルバミン酸、炭酸、リン酸トリエステル、アセトアミデート、カルボキシメチルエステル、およびそれらの組み合わせから選択される修飾されたヌクレオチドを含む複数の修飾を含む、請求項17に記載のオリゴヌクレオチド。   A modified nucleotide selected from phosphorothioate, alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamic acid, carbonic acid, phosphate triester, acetamidate, carboxymethyl ester, and combinations thereof 18. The oligonucleotide of claim 17, comprising a plurality of modifications comprising. ペプチド核酸、ロックド核酸(LNA)、類似体、誘導体、およびそれらの組み合わせから選択される修飾されたヌクレオチドを含む複数の修飾を含む、請求項17に記載のオリゴヌクレオチド。   18. The oligonucleotide of claim 17, comprising a plurality of modifications, including modified nucleotides selected from peptide nucleic acids, locked nucleic acids (LNA), analogs, derivatives, and combinations thereof. 2'-O-メトキシエチル修飾糖部分、2'-メトキシ修飾糖部分、2'-O-アルキル修飾糖部分、二環性糖部分、およびそれらの組み合わせから選択される少なくとも1つの修飾された糖部分を含む、請求項17に記載のオリゴヌクレオチド。   At least one modified sugar selected from 2'-O-methoxyethyl modified sugar moieties, 2'-methoxy modified sugar moieties, 2'-O-alkyl modified sugar moieties, bicyclic sugar moieties, and combinations thereof 18. The oligonucleotide of claim 17, comprising a moiety. 2'-O-メトキシエチル修飾糖部分、2'-メトキシ修飾糖部分、2'-O-アルキル修飾糖部分、二環性糖部分、およびそれらの組み合わせから選択される修飾された糖部分を含む複数の修飾を含む、請求項17に記載のオリゴヌクレオチド。   Includes a modified sugar moiety selected from 2'-O-methoxyethyl modified sugar moieties, 2'-methoxy modified sugar moieties, 2'-O-alkyl modified sugar moieties, bicyclic sugar moieties, and combinations thereof 18. The oligonucleotide of claim 17, comprising a plurality of modifications. 長さ少なくとも5〜30ヌクレオチドのオリゴヌクレオチドであり、腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドのアンチセンス鎖および/またはセンス鎖にハイブリダイズし、腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドのアンチセンスおよび/またはセンスのコードおよび/または非コード核酸配列の少なくとも5個の連続する核酸の相補配列に少なくとも20%の配列同一性を有する、請求項17に記載のオリゴヌクレオチド。 An oligonucleotide of at least 5 to 30 nucleotides in length that hybridizes to the antisense strand and / or sense strand of a tumor necrosis factor receptor 2 (TNFR2) polynucleotide and also has a 2 0% sequence identity to as least the five complementary sequence of contiguous nucleic acids less of antisense and / or sense of coding and / or non-coding nucleic acid sequences, oligonucleotide according to claim 17 . 腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドのアンチセンスおよび/またはセンスのコードおよび/または非コード核酸配列の少なくとも5個の連続する核酸の相補配列に少なくとも80%配列同一である、請求項17に記載のオリゴヌクレオチド。 Tumor Necrosis Factor Receptor 2 (TNFR2) polynucleotide antisense and / or sense code and / or a small non-coding nucleic acid sequence also five and even 80% sequence identity less complementary sequences of contiguous nucleic acid 18. The oligonucleotide according to claim 17, wherein 少なくとも1つの腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドにハイブリダイズし、かつ正常対照と比較してin vivoまたはin vitroで少なくとも1つの腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドの発現および/または機能を調節する、請求項17に記載のオリゴヌクレオチド。   Expression of and / or at least one tumor necrosis factor receptor 2 (TNFR2) polynucleotide in vivo or in vitro relative to at least one tumor necrosis factor receptor 2 (TNFR2) polynucleotide and compared to a normal control 18. The oligonucleotide of claim 17, which modulates function. 配列番号4〜10に記載の配列を含む、請求項17に記載のオリゴヌクレオチド。   18. The oligonucleotide of claim 17, comprising the sequence set forth in SEQ ID NOs: 4-10. アンチセンス配列、相補配列、対立遺伝子、相同体、アイソフォーム、変種、誘導体、変異体、断片またはそれらの組み合わせを含む、1つまたは複数の腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドに特異的な1つまたは複数のオリゴヌクレオチドを含む組成物。   Specific for one or more tumor necrosis factor receptor 2 (TNFR2) polynucleotides, including antisense sequences, complementary sequences, alleles, homologues, isoforms, variants, derivatives, variants, fragments or combinations thereof A composition comprising one or more oligonucleotides. オリゴヌクレオチドが、配列番号4〜10に記載のヌクレオチド配列のいずれか1つと比較して少なくとも40%の配列同一性を有する、請求項30に記載の組成物。 Oligonucleotide has a 4 0% sequence identity also less with any one comparison of the nucleotide sequence set forth in SEQ ID NO: 4-10, composition according to claim 30. オリゴヌクレオチドが、配列番号4〜10に記載のヌクレオチド配列を含む、請求項30に記載の組成物。   31. The composition of claim 30, wherein the oligonucleotide comprises the nucleotide sequence set forth in SEQ ID NOs: 4-10. 配列番号4〜10に記載のオリゴヌクレオチドが、1つまたは複数の修飾または置換を含む、請求項32に記載の組成物。   33. The composition of claim 32, wherein the oligonucleotides set forth in SEQ ID NOs: 4-10 comprise one or more modifications or substitutions. 1つまたは複数の修飾が、ホスホロチオエート、メチルホスホネート、ペプチド核酸、ロックド核酸(LNA)分子およびそれらの組み合わせから選択される、請求項33に記載の組成物。   34. The composition of claim 33, wherein the one or more modifications are selected from phosphorothioates, methyl phosphonates, peptide nucleic acids, locked nucleic acid (LNA) molecules, and combinations thereof. 少なくとも1つの腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドおよび/または少なくとも1つのそのコード産物に関連する疾患を予防するまたは治療するための組成物であって、
前記少なくとも1つの腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドの天然アンチセンス配列に結合し、かつ前記少なくとも1つの腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドの発現を調節する少なくとも1つのアンチセンスオリゴヌクレオチドの治療有効量を含む組成物。 A composition for preventing or treating a disease associated with at least one tumor necrosis factor receptor 2 (TNFR2) polynucleotide and / or at least one encoded product thereof , comprising:
At least one antisense that binds to a natural antisense sequence of said at least one tumor necrosis factor receptor 2 (TNFR2) polynucleotide and modulates expression of said at least one tumor necrosis factor receptor 2 (TNFR2) polynucleotide therapeutically effective amount including composition of the oligonucleotide. 少なくとも1つの腫瘍壊死因子受容体2(TNFR2)ポリヌクレオチドに関連する疾患が、癌、細胞増殖に関連する、または細胞増殖を特徴とする疾患または状態、TNFRSF1B/TNFR2の突然変異体または異常な発現または機能に関連する疾患または障害、神経疾患または障害、自己免疫疾患または障害、免疫系に関連する疾患または障害、炎症性腸疾患、多遺伝子性の感受性を伴う慢性的な炎症性の状態(クローン病、潰瘍性大腸炎を含む)、過剰なサイトカイン活性に関連する疾患または障害、悪液質、肝疾患、腎疾患(糸球体腎炎、急性腎臓移植片拒絶、急性尿細管壊死を含む)、循環器の疾患または障害、虚血介在性の動脈形成および血管形成、酸化ストレス、炎症、脳マラリア、炎症に関連する疾患、障害または状態(関節リウマチ、乾癬および乾癬性関節炎、クローン病、潰瘍性大腸炎、慢性炎症誘導性の結腸上皮変質を含む)から選択される、請求項35に記載の組成物。 A disease or condition associated with at least one tumor necrosis factor receptor 2 (TNFR2) polynucleotide is associated with or characterized by cancer, cell proliferation, a mutant or abnormal expression of TNFRSF1B / TNFR2 or functions related to the disease or disorder, neurological disease or disorder, an autoimmune disease or disorder, a disease or disorder associated with the immune system, inflammatory bowel disease, chronic inflammatory conditions (click with polygenic susceptibility Crohn's disease, ulcerative colitis), diseases or disorders associated with excessive cytokine activity, cachexia, liver disease, kidney disease (including glomerulonephritis, acute renal transplant rejection, acute tubular necrosis), cardiovascular diseases or disorders, ischemia mediated arteriogenesis and angiogenesis, oxidative stress, inflammation, cerebral malaria, diseases associated with inflammation, disorder or condition (Takashi Seki arthritis, psoriasis and psoriatic arthritis 36. The composition of claim 35, comprising : Crohn's disease, ulcerative colitis, chronic inflammation-induced colonic epithelial alteration). In vivo投与のために少なくとも1つのオリゴヌクレオチドを同定および選択する方法であって、病態に関連する標的ポリヌクレオチドを選択するステップ;選択された標的ポリヌクレオチドまたは選択された標的ポリヌクレオチドにアンチセンスであるポリヌクレオチドに相補的である少なくとも5個の連続するヌクレオチドを含む少なくとも1つのオリゴヌクレオチドを同定するステップ;ストリンジェントなハイブリダイゼーション条件下における、アンチセンスオリゴヌクレオチドと標的ポリヌクレオチドまたは選択された標的ポリヌクレオチドにアンチセンスであるポリヌクレオチドのハイブリッドの熱的融点を測定するステップ;ならびに得られた情報に基づいてin vivo投与のための少なくとも1つのオリゴヌクレオチドを選択するステップ
を含む方法。 A method of identifying and selecting at least one oligonucleotide for in vivo administration, comprising selecting a target polynucleotide associated with a disease state; antisense to a selected target polynucleotide or a selected target polynucleotide Identifying at least one oligonucleotide comprising at least 5 contiguous nucleotides that are complementary to a polynucleotide; under stringent hybridization conditions, the antisense oligonucleotide and the target polynucleotide or selected target polynucleotide Measuring the thermal melting point of a hybrid of a polynucleotide that is antisense to a nucleotide; and selecting at least one oligonucleotide for in vivo administration based on the information obtained. No way.
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